Following the rapid developments in biotechnology and genetic engineering within the last years, a large number of proteins and peptides of potential therapeutic use has been made available. However, the delivery of protein and peptide pharmaceuticals to patients is not easy to accomplish, largely due to their inherent physical and chemical instability. Upon oral administration to a patient, they undergo degradation due to hydrolysis in the acidic environment of the stomach, so that their activity in the gastrointestinal tract is significantly reduced. A relatively fast inactivation can also be observed after parenteral, in particular intravenous presentation which is due to the short half-life of many active substances. As a consequence, repeated high dosages of these compounds may be required in spite of their high pharmacological activity, which represents a significant burden for the patient. Compliance problems are furthermore obviated if the number of dosages can be reduced.
As suitable formulations overcoming the above-mentioned drawbacks, sustained release systems in the form of microspheres are known which control the release of the active substance by incorporating it in a shell or a matrix of a biodegradable polymer. Such formulations are most commonly provided via formation of microspheres by the “water-in-oil-in-water” (W/O/W) technique (e.g as disclosed in EP-A-442 671). However, it has become increasingly apparent that the protein solutions emulsified in the oil phase suffer from degradation due to denaturation of the protein structures at the water/oil interface during the preparation of the capsules. Furthermore, the influence of shear forces during emulsification may also contribute to a loss of active material.
In view of these problems, encapsulation strategies have been developed that try to minimize the exposure of hydrated proteins to physical stress factors, based on the finding that proteins in a crystalline or amorphous form are less susceptible to denaturation. Methods using the increased stability of proteins in their solid state have been published, e.g., by T. Morita et al., Eur. J. Pharm. Sci. 88 (1999) 45-53 or I. J. Castellanos et al., J. Pharm. Pharmacol., 53 (2001) 167-178. According to these “solid-in-oil-in-water” (S/O/W) techniques, proteins are suspended in an organic solution of the biodegradable polymer, followed by emulsification of the suspension in an aqueous solution and formation of solid microspheres via removal of the organic solvent. However, the S/O/W-technique as applied therein requires solutions of the active substance to be pretreated by micronization, spray drying or lyophilisation in order to obtain a powder suitable for being suspended in the polymer solution. Moreover, the flexibility of these methods with respect to an optimization of release properties of the final formulation is impaired, since the range for selective variations of particle size within these powders is frequently restricted by the type of apparatus used for their provision.
As a consequence, there is still a need for methods for the encapsulation of sensitive active substances which, while avoiding as far as possible complicated and time consuming process steps, allow the encapsulation of the active substances at a high efficiency and on an industrial scale. Moreover, the method should ensure control of release kinetics of the active substances, and, at the same time, allow the adaptation of these kinetics to different types of active substances and different therapeutical applications. It is finally also an object to overcome compliance problems which are especially encountered with elder patients.